Obesity, which is caused by the abnormal accumulation of fat in fat tissue and in various organs in the human body, is considered to be closely associated with the onset of various lifestyle-related diseases such as hypertension, arteriosclerosis, and diabetes. Further, obesity is becoming a problem in the field of cosmetics because it alters body proportions and significantly impairs the outward appearance.
Obesity is said to be caused by the accumulation of fat due to the consumption of excess calories over calories used, which is the result of predisposing factors such as constitutional, dietary, mental, central, and metabolic factors, a lack of exercise, and the like. In obesity, the amount of fat that accumulates in individual adipocytes, namely triglyceride, is increased and the adipocytes are enlarged. Furthermore, it has recently been elucidated that the number of adipocytes continues to increase after adulthood. Thus, it is anticipated that obesity can be improved by decreasing the number of mature adipocytes by inhibiting the differentiation of preadipocytes into mature adipocytes, and that the progression of obesity can be suppressed by inhibiting fat accumulation in mature adipocytes.
Examples of medicines, food, or cosmetic agents that exert an anti-obesity effect by inhibiting the increase in the number of adipocytes include one that contains preadipocyte differentiation-inhibitory peptides as an active ingredient (refer to Patent Document 1) and one that contains activated whey as an active ingredient (refer to Patent Document 2). Further, an attempt has been made to apply ω-3-based polyunsaturated fatty acids as an active agent to the skin (refer to Patent Document 3). Also, it was reported that arterenol acted on β3 adrenaline distributed in adipocytes to trigger the activation of protein kinase A (PKA) and hormone-sensitive lipase (HSL), which promoted the degradation of triglyceride that had accumulated as an oil droplet (refer to Non-Patent Document 1).
The present inventors have continuously studied medicines and other products that exhibit an anti-obesity effect by inhibiting the differentiation of preadipocytes or inhibiting fat accumulation in adipocytes, and have found a preadipocyte differentiation-inhibitory agent containing an active ingredient extracted from a specific mushroom or plant (Patent Document 4), an adipocyte differentiation-inhibitory agent containing ternatin: cyclo[-D-Ile1-(N-Me)-L-Ala2-(N-Me)-L-Leu3-L-Leu4-(N-Me)-L-Ala5-(N-Me)-D-Ala6-β-OH-D-Leu7-], which is a cyclic heptapeptide, as an active ingredient (Patent document 5), and an adipocyte differentiation-inhibitory agent containing bisabololoxide-A-β-glucoside, which is a plant ingredient, as an active ingredient (Patent Document 6). However, before cyclic peptides with the aforementioned properties can be put to practical application, various tests as well as the development and investigation of analogous compounds that may be even more efficacious are necessary. Thus, the development of an inexpensive, high-yield production method is needed because the amount of cyclic peptides as described above that can be obtained from natural sources has been insufficient. The physical properties and results of the X-ray crystal structure analysis of ternatin have been reported (refer to Patent Document 7, Non-Patent Documents 2 and 3).
In general, methods for the synthesis of a peptide (production method) include both solid-phase and solution-phase methods. Both methods have good and bad points. Although the present inventors initially synthesized ternatin by a solid-phase method and determined its stereochemical structure (Non-Patent Document 4), the yield was low, a reagent used was expensive, the method was inefficient because every time an analogous compound in which some of the constituent amino acids were replaced was synthesized, it needed to be synthesized sequentially from one end, and the like.    [Patent Document 1] Japanese Patent Application Laid-Open No. 6-293796    [Patent Document 2] Japanese Patent Application Laid-Open No. 2002-37738    [Patent Document 3] Japanese Patent Application Laid-Open No. 11-130656    [Patent Document 4] Japanese Patent Application Laid-Open No. 2004-075640    [Patent Document 5] Japanese Patent Application Laid-Open No. 2005-220074    [Patent Document 6] Japanese Patent Application Laid-Open No. 2006-213648    [Patent Document 7] Russian Patent No. N517198, Specification, 1974.    [Non-Patent Document 1] Protein Nucleic Acid Enzyme 2000, 45, 935-940.    [Non-Patent Document 2] Acta Crystallographica Section D, 1993, 49, 158-167.    [Non-Patent Document 3] International Journal of Peptide & Protein Research, 1993, 42, 539-549.    [Non-Patent Document 4] Tetrahedron Letters, 2006, 47, 4445.